SLERT, as a novel biomarker, orchestrates endometrial cancer metastasis via regulation of BDNF/TRKB signaling

Abstract

BackgroundRecent evidence suggests that the box H/ACA small nucleolar RNA (snoRNA)-ended long noncoding RNA (lncRNA), SLERT, plays a critical role in gene regulation. However, its role in cancer remains undetermined. Herein, we explored its implication in human endometrial cancer (EC).MethodsEC plasma and tissue samples were collected for the detection of SLERT expression using qRT-PCR method. The functional investigation was tested by CCK-8 and transwell assays. Luciferase reporter, RNA pull-down, and immunoprecipitation (RIP) assays were used to determine the regulatory network involved in SLERT. The in vivo effect of SLERT was tested by caudal vein lung metastasis model.ResultsStable knockdown of SLERT significantly inhibited EC cell (KLE and AN3CA) migration and invasion, while it did not affect cell viability. SLERT induced epithelial-mesenchymal transition (EMT) via elevating N-cadherin and Vimentin and downregulating E-cadherin. Further investigation showed that SLERT directly binds to METTL3, increasing the m6A levels of BDNF mRNA; then, the m6A sites were read by IGF2BP1, enhancing BDNF mRNA stability, followed by the activation of BDNF/TRKB signaling, an inducer of EMT. The animal model showed that overexpression of SLERT increased EC cell lung metastasis, and this effect was effectively blocked by BDNF silencing or treatment with TRKB inhibitor k252a. Clinically, EC patients have high levels of SLERT both in tissue or plasma, which might be used as a biomarker of diagnosis and prognosis.ConclusionOur findings, for the first time, uncover the metastasis-promoting effect of SLERT in EC via in vitro and in vivo evidence, providing a potential therapeutic target for metastatic EC treatment.